title: Regulation of magnesium reabsorption in DCT.
abstract: The distal convoluted tubule (DCT) is the shortest segment of the nephron and consists of an early (DCT1) and late part (DCT2). Here, several transport proteins, like the thiazide-sensitive NaCl cotransporter (NCC) and the epithelial magnesium (Mg(2+)) channel (TRPM6), are exclusively expressed. This makes the DCT the major site of active transcellular Mg(2+) reabsorption determining the final excretion in the urine. Following the Mg(2+) influx via the apically localized TRPM6, intracellular Mg(2+) diffuses to the basolateral membrane where it is extruded to the blood compartment via still-unidentified Mg(2+) transporters. Recent years have witnessed multiple breakthroughs in the field of transcellular Mg(2+) reabsorption. Epidermal growth factor and estrogen were identified as magnesiotropic hormones by their effect on TRPM6 activity. Intracellularly, receptor of activated protein kinase C 1 and adenosine triphosphate were shown to inhibit TRPM6 activity through its alpha-kinase domain. Furthermore, dysregulation or malfunction of transcellular Mg(2+) reabsorption in DCT has been associated with renal Mg(2+) wasting. Mutations in TRPM6 are responsible for hypomagnesemia with secondary hypocalcemia. A defect in the gamma-subunit of the Na(+)/K(+)-adenosine triphosphatase causes isolated dominant hypomagnesemia resulting from renal Mg(2+) wasting. Moreover, in Gitelman's syndrome, mutations in NCC also result in impaired transcellular Mg(2+) reabsorption in DCT. This review highlights our recently obtained knowledge concerning the molecular regulation of transcellular Mg(2+) reabsorption.
authors.affiliation: Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xi
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: René J M
authors.initials: RJ
authors.lastname: Bindels
mesh_terms: D000818:Animals; D004058:Diffusion; D004815:Epidermal Growth Factor / Q000235:genetics / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D008274:Magnesium / Q000097:blood / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D028021:Sodium-Potassium-Chloride Symporters; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; D004815:Epidermal Growth Factor; D011494:Protein Kinases; D019204:GTP-Binding Proteins; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium